The pharmacological profile of a novel
cyclic nucleotide phosphodiesterase (PDE) inhibitor,
Org 20241, has been characterized. The compound selectively inhibits PDE IV (pIC50, 5.2-6.1) and PDE III (pIC50, 4.4-4.6) from animal and human tissues.
Org 20241 relaxed preparations of bovine trachea (pD2, 5.9 and 5.4), guinea pig trachea (pD2, 6.2 and 4.9) and human bronchi (pD2, 5.3 and 4.7) for
histamine and
methacholine-induced contractions, respectively.
Rolipram and
Org 20241 inhibited
leukotriene B4-induced thromboxaneB2 (IC50, 0.3 and 1.4 microM, respectively) and H2O2 (IC50, 2.1 and 0.4 microM, respectively) production in guinea pig eosinophils. In
phenylephrine (0.3 microM) precontracted rabbit aorta preparations, the PDE III inhibitor
Org 9935 (pD2, 6.3 and 6.1 in the presence and absence of endothelium, respectively) was the most effective relaxant, whereas
Org 20241 (pD2, 5.3 and 5.4 in the presence and absence of endothelium, respectively) was more effective than
rolipram (pD2, 4.6 and 4.1 in the presence and absence of endothelium, respectively).
Org 20241 relaxed rabbit aorta preparations and airway preparations at similar concentrations. In electrically stimulated rabbit cardiac papillary muscles,
Org 20241 had little effect on contractility at concentrations up to 30 microM. Lower concentrations (10 microM) potentiated the inotropic effect of
Org 9935. Whereas the PDE III inhibitor
milrinone (1-100 microM) enhanced the rate of repolarization of guinea pig papillary muscles and shortened the effective refractory period,
Org 20241 and
rolipram (1-100 microM) did not reduce the action potential duration. In the presence of
Org 20241 or
rolipram,
isoproterenol did not produce a greater increase in the rate of repolarization or reduction in the effective refractory period than in the absence of these PDE inhibitors.
Org 20241 is a dual PDE IV/III inhibitor with some PDE IV selectively. This compound relaxes airways smooth muscle and inhibits eosinophil activation. The data indicate that such PDE IV/III inhibitors may be effective for the long-term
therapy of
asthma.